JP4674297B2 - Method for producing D-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative - Google Patents

Description

  The present invention relates to a method for producing a highly pure D-erythro-2,2-difluoro-2-deoxy-1-oxoribose derivative.

D-erythro-2,2-difluoro-2-deoxy-1-oxoribose is a therapeutic agent for non-small cell lung cancer to produce gemcitabine of the following formula (A) It is an important intermediate used.

  Gemcitabine is an erythro enantiomer having a 3-hydroxy functional group that is downward (position on the tetrohydrofuran ring is opposite to the 5-hydroxy group), so that in the production of gemcitabine, 3- It is important to develop a method for producing a 1-oxoribose erythro compound having a hydroxy group.

前記式中、
Ｒ^４及びＲ^５はそれぞれ独立的にＣ_１−３アルキルである。 US Pat. No. 4,526,988 is 2,2-difluoro, which is a 3: 1 mixture of 3R-hydroxy optical isomer of the following formula (B) and 3S-hydroxy optical isomer of the following formula (B ′) Disclosed is a method for preparing erythro 1-oxoribose compounds through alkyl-3-hydroxy-3- (2,2-dialkyldioxolan-4-yl) propionate:

In the above formula,
R ⁴ and R ⁵ are each independently C _1-3 alkyl.

However, in such a method, the compounds of the formulas (B) and (B ′) react with an acid as shown in the following reaction formulas A and B, respectively, and erythro compounds of the formula (C) and To produce the threo compound of formula (C ′), a mixture of compounds of formula (B) and (B ′) is used to selectively produce the desired erythro 1-oxoribose derivative. Comprising an uneconomical step to separate only the 3R-hydroxy optical isomers.

  In addition, the above method has a problem that a long reaction time, that is, the reaction must be performed at room temperature for about 4 days.

前記式中、Ｂｚはベンゾイルである。 On the other hand, in US Pat. Nos. 4,965,374, 5,223,608 and 5,434,254, as shown in the following reaction formula C, (i) 3-benzoyl of the following formula (E) Hydrolysis and azeotropic distillation of oxypropionic acid ester (3: 1 mixture of 3R- and 3S-enantiomers) to obtain a lactone compound of formula (F) below; (ii) Formula (F ) Protecting the 5-hydroxy group of the compound with benzoyl to obtain a 3,5-dibenzoyloxy compound of formula (G); and (iii) cooling the compound of formula (G) to −5 to 10 ° C. Discloses a method for obtaining an erythro optical isomer of the following formula (D), which comprises the step of precipitating only the erythro optical isomer of the following formula (D).

In the above formula, Bz is benzoyl.

  However, this method has an overall yield as low as about 25% and is uneconomic due to the overuse of expensive and toxic trifluoroacetic acid in the hydrolysis process.

前記式中、Ｒ^６〜Ｒ^９はアルキルであり；Ｒ^１０及びＲ^１１はＣ_１−３アルキルである。 In US Pat. Nos. 5,428,176 and 5,618,951, 2,2-difluoroketene silyl acetal is converted to 1,3-dimethylpropylene urea (DMPU) as shown in the following reaction formula D. 2,2-difluoro-β-silyloxy-1,3-dioxolane-4-propion of the following formula (H) containing a high volume of 3R-silylhydroxy optical isomer by reacting with a glyceraldehyde derivative in such a solvent A method for producing acid esters is presented.

Wherein R ^{6 to} R ⁹ are alkyl; R ¹⁰ and R ¹¹ are C _1-3 alkyl.

  However, the above method also has a problem that it requires an uneconomical column chromatography step for separating only the 3R-optical isomer from the mixture of optical isomers.

Accordingly, as a result of intensive studies to develop an efficient method capable of selectively producing a 1-oxoribose compound having an erythro structure, the present inventors have obtained 2,2-difluoro-2- having a high purity erythro structure. An efficient and novel method for producing deoxy-1-oxoribose was found and the present invention was completed.
U.S. Pat. No. 4,526,988 U.S. Pat. No. 4,965,374 US Pat. No. 5,223,608 US Pat. No. 5,434,254 US Pat. No. 5,428,176 US Pat. No. 5,618,951

Accordingly, an object of the present invention is to provide an efficient method for selectively producing 2,2-difluoro-2-deoxy-1-oxoribose derivatives having an erythro structure.
Another object of the present invention is to provide 3R-optical isomer compounds that can be used as intermediates in the process.

In order to achieve the above object, the present invention
(i) reacting a compound of formula (V) with a biphenylcarbonyl derivative to obtain a compound of formula (IV) having a 3-hydroxy group protected with a biphenylcarbonyl group;
(ii) reacting the compound of the formula (IV) with a base in a mixed solvent essentially containing water to obtain a 3R-carboxylate enantiomer of the formula (III);
(iii) reacting the compound of formula (III) with an acid to give a 5-hydroxy-1-oxoribose derivative of formula (II); and
(iv) a 2,2-difluoro-2-deoxy-1-oxoribose derivative of formula (I) comprising the step of protecting the 5-hydroxy group of the compound of formula (II) with R ³ Manufacturing method:

であり；
Ｒ^１はメチル又はエチルであり；
Ｒ^２はＣ_１−３アルキルであり；
Ｒ^３はベンゾイル又は

であり；
Ｒ^４はフェニル又は置換されたフェニルであり；及び
Ｍはアンモニウム(ＮＨ_４)、ナトリウム又はカリウムである。 In the above formula,
R is

Is;
R ¹ is methyl or ethyl;
R ² is C _1-3 alkyl;
R ³ is benzoyl or

Is;
R ⁴ is phenyl or substituted phenyl; and M is ammonium (NH ₄ ), sodium or potassium.

前記式中、
Ｒ，Ｒ^１及びＭは前記で定義された通りである。 In order to achieve the other object, the present invention provides a 3R-carboxylate optical isomer of the following formula (III):

In the above formula,
R, R ¹ and M are as defined above.

  The method for producing a 1-oxoribose derivative having an erythro structure according to the present invention is a method showing very excellent stereoselectivity as compared with a conventional production method, in particular from a 3-hydroxyester compound of the formula (V) Since the total reaction yield of 2,2-difluoro-2-deoxy-1-oxoribose of (I) is 45-50%, which is greatly improved by 20% or more compared with the conventional method, it is very economical. Is an efficient and efficient method.

  In the production method according to the present invention, the compounds of the following formulas (IV) and (V) are a mixture of 3R- and 3S-optical isomers in a specific ratio.

前記式中、Ｒ、Ｒ^１、Ｒ^２、Ｒ^３及びＭは前記で定義された通りである。 The process of the present invention is shown schematically in Scheme I below.

In the above formula, R, R ¹ , R ² , R ³ and M are as defined above.

  In the reaction formula I, a step of obtaining a compound of the formula (IV) by protecting the 3-hydroxy group of the compound of the formula (V) with a biphenylcarbonyl group; the compound of the formula (IV) is hydrolyzed with a base. In order to obtain the 3R-carboxylate of formula (III), in which case only the 3R-optical isomer is obtained as a solid, so that from the reaction mixture of 3R- and 3S-optical isomers, the 3R- of formula (III) An optical isomer can be separated; the dioxolane group of the compound of the formula (III) is deprotected with an acid to obtain a carboxylic acid derivative, and the carboxylic acid derivative is lactonized while distilling off water to give an erythro structure Obtaining a 5-hydroxy-1-oxoribose of the formula (II) having the formula; and protecting the 5-hydroxy group of the compound of the formula (II) by conventional methods. -Difluoro-2-deoxy A -1-oxoribose derivative can be produced in high yield.

  A feature of the present invention is that the 3R-carboxylate optical isomer of formula (III) can be selectively obtained by protecting the 3-hydroxy group of the compound of formula (V) with a biphenylcarbonyl group, This gives a 1-oxoribose derivative of formula (I) having the desired erythro structure.

前記式中、Ｒ、Ｒ^１及びＲ^２は前記で定義された通りである。 In the method of the present invention, the compound of formula (III) is selectively obtained as a solid, so that it can be easily separated using a simple filtration step without uneconomic column chromatography or other purification steps. Can do. Therefore, the use of the compound of formula (II) as an intermediate is an inherent feature unique to the method of the present invention suitable for mass production of 1-oxoribose derivatives.
The compound of the formula (V) used as a starting material in the method of the present invention is shown in the following reaction formula II. US Pat. Nos. 4,526,988, 4,965,374, 5,223, It can be prepared by the usual methods presented in 608 and 5,434,254.

In the above formula, R, R ¹ and R ² are as defined above.

  In Formula II above, the compound of formula (V), which is a 3: 1 mixture of 3R- and 3S-optical isomers, is obtained by mixing an aldehyde ketonide of formula (VII) with a difluoro compound of formula (VI); The mixture can be prepared by performing a Reformatsky reaction using zinc.

前記式中、Ｒ、Ｒ^１、Ｒ^２及びＭは前記で定義された通りである。 Further, as shown in the following reaction formula III, the 3R-carboxylate salt of the formula (III) can be produced from the compound of the formula (V).

In the above formula, R, R ¹ , R ² and M are as defined above.

  In the reaction formula III, the 3R-carboxylate salt of the formula (III) comprises (i) a step of obtaining a compound of the formula (IV) by protecting the 3-hydroxy group of the compound of the formula (V) with a biphenylcarbonyl protecting group. And (ii) can be obtained as a solid by hydrolyzing the compound of formula (IV) with a base.

  In the method of the present invention, the protecting group used in the step (i) may be a biphenylcarbonyl group which is a benzoyl group substituted with a benzene ring, wherein the benzene ring is hydrogen, cyano, halo. , Carboalkoxy, toluoyl, nitro, alkoxy, alkyl, and dialkylamino can be selectively substituted with at least one substituent. Representative examples of the biphenylcarbonyl include 2-phenylbenzoyl (2-biphenylcarbonyl), 4-phenylbenzoyl (4-biphenylcarbonyl) and substituted 2- (or 4-) phenylbenzoyl, preferably 2 -Phenylbenzoyl and 4-phenylbenzoyl.

  Since the two benzene rings of the biphenylcarbonyl group are included, the hydrophobicity is increased, so that the 3R-carboxylate salt of the formula (III) can be separated as a solid in water or a mixed solvent containing water.

  On the other hand, when a normal benzoyl group is used as the hydroxy protecting group, it is impossible to obtain the 3R-carboxylate as a solid in water or a mixed solvent containing water.

  In contrast, when a conventional hydroxy protecting group such as 1-naphthoyl, 2-naphthoyl, pivaloyl or acetyl group is introduced as the 3-hydroxy group of the compound of formula (V), it was generated. It is very difficult to selectively separate the 3R-carboxylate salt of formula (III) as a solid from the reaction mixture.

  The biphenylcarbonyl compound used in step (i) can be selected from the group consisting of chloride, bromide, cyanide or azide of biphenylcarbonyl (or substituted biphenylcarbonyl), which are commercially available Or can be chemically synthesized by conventional methods.

  The base used in the neutralization step in step (i) can be selected from the group consisting of pyridine, triethylamine, tributylamine, diisopropylethylamine and methylpiperidine, preferably triethylamine; catalyst used in the acylation reaction May be 4-dimethylaminopyridine or 4-pyrrolidinopyridine; the acylation reaction may be carried out at -25 to 50 ° C.

  In the hydrolysis reaction of step (ii), the base is selected from the group consisting of gaseous ammonia, aqueous ammonia, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, potassium hydroxide and mixtures thereof. Preferably, potassium bicarbonate is used. This can be used in an amount of 1 equivalent or more, preferably 1.5 to 5 equivalents, relative to the compound of formula (IV).

  In addition, water and a mixed solvent that essentially contains water are water, tetrahydrofuran, dioxane, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide, ethyl acetate, and mixtures thereof. A mixture of organic solvents selected from the group consisting of water, tetrahydrofuran and methanol; preferably water is used in an amount of 3-15 ml, preferably 5-11 ml, relative to 1.0 g of the compound of formula (IV) The organic solvent can be used in the range of 3-30 ml, preferably 6-18 ml. The hydrolysis reaction may be performed at 5 to 50 ° C, preferably 10 to 30 ° C for 30 minutes to 2 hours.

  The compound of formula (III) is obtained by removing the organic solvent under reduced pressure and filtering the resulting mixture, or extracting the reaction mixture with an organic solvent, and then reusing the product in a mixed solvent essentially containing water. By crystallizing it can be easily separated from the reaction mixture obtained in step (ii).

  In the process of the invention, the 3R-carboxylate salt of formula (III) is obtained in a high yield of 60-70% from the compound of formula (V) when using potassium or sodium salt in step (ii). When an ammonium salt is used, the yield is about 40%. Further, the compound of the formula (III) obtained by the method of the present invention has a 3S-carboxylate content of less than 0.3%, whereas the 3R-carboxylate content is 99.7% or more. Yes (as a result, an ee value of 99.4% or more).

前記式中、Ｒ、Ｒ^１、Ｒ^３及びＭは前記で定義された通りである。 A compound of formula (I) having an erythro structure can be obtained in a highly enantioselective manner from a compound of formula (III) as shown in Reaction Scheme IV below.

In the above formula, R, R ¹ , R ³ and M are as defined above.

 In the reaction formula IV, the compound of the formula (I) is produced by reacting the compound of the formula (III) with an acid in a solvent to neutralize a carboxylate salt and produce a diol carboxylic acid of the formula (VIII) Performing a cascade of reaction comprising removal of the isoalkylidene protecting group to effect and lactonization of the compound of formula (VIII) to obtain a compound of formula (II) having an erythro structure; and (iv ) It can be prepared by protecting the 5-hydroxy group of the compound of formula (II) with a protecting group containing a hydrophobic benzene ring.

  The acid used in step (iii) of the present invention may be a strong acid having a pka value in the range of -10.0 to 2.0; for example, inorganic acids such as 1N to 12N hydrochloric acid and 1N to 9N sulfuric acid. Selected from the group consisting of organic acids such as methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid, preferably 12N hydrochloric acid and trifluoroacetic acid, more preferably 12N hydrochloric acid; It is used in the range of 1 to 2 equivalents, preferably 1.1 to 1.5 equivalents, relative to the compound of formula (III).

  On the other hand, in order to effectively remove the isoalkylidene group, the reaction product of the step (iii) is added with an aqueous solution such as an inorganic acid aqueous solution or 95% ethanol having an appropriate concentration to the reaction product. In this way, the amount of water may be adjusted to 1 to 10 equivalents, preferably 2 to 5 equivalents, relative to the compound of the formula (III). The solvent used in step (iii) may be selected from the group consisting of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethanol, methanol and isopropanol, preferably acetonitrile.

  Removal of the isoalkylidene group in step (iii) is carried out at the reflux temperature of the solvent for 4-8 hours; the resulting mixture is mixed with a solvent such as benzene and toluene and then azeotropically distilled to remove water from the reaction mixture. Thus, a lactonized compound of the formula (II) is obtained.

In step (iv), the protecting group is selected from the group consisting of benzoyl, phenylbenzoyl and substituted benzoyl, preferably 2-phenylbenzoyl, 4-phenylbenzoyl and substituted 2- (or 4-) phenylbenzoyl. be able to.
In addition, step (iv) can be performed after the compound of formula (II) obtained in step (iii) is separated, but can be performed in situ without such separation step. In this case, an in situ process is preferable.

  The compound of formula (I) obtained by the method of the present invention is a 1-oxoribose compound having a desired erythro structure with a purity of about 99%.

  Also, the method of the present invention has an overall yield of 45 to 50%, which is 20% or more higher than the conventional method.

  The invention will now be described in detail by the following examples. However, the examples are only for illustrating the present invention and are not intended to limit the scope of the present invention.

Production Example 1
Preparation of 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxolan-4-yl) propionate (compound of formula (V))
Stage 1
Preparation of 1,2-bis- (2,2-dimethyl-1,3-dioxolan-4-yl) -ethane-1,2-diol

100 g of d-mannitol is mixed with 160 ml of 2,2-dimethoxypropane, 240 ml of 1,2-dimethylethanediol and 0.1 g of anhydrous SnCl ₂ , the mixture is heated until a homogeneous solution is obtained and then refluxed for 30 minutes. Was added with 0.2 ml of pyridine. The reaction mixture was allowed to cool to room temperature and then distilled under reduced pressure to remove the solvent. To the residue was added 700 ml of methyl chloride and refluxed for 1 hour. The resulting mixture was filtered through 10 g of Celite at room temperature, and then the filtrate was distilled under reduced pressure to remove the solvent. The residue was recrystallized from 1 L of hexane, filtered and dried to obtain 72.4 g (yield: 50%) of the title compound as a white solid.
NMR (300 MHz, CDCl ₃ ): 1.30 (s, 6H), 1.36 (s, 6H), 2.52 (d, 2H), 3.67 (t, 2H), 3.91 (m, 2H), 4.04 to 4.14 (m, 4H)
Melting point (mp): 119-121 ° C

前記段階１で得られた化合物７２．４ｇを塩化メチル７２４ｍｌに溶解した後、これに飽和重炭酸ナトリウム３０ｍｌを加えた。前記混合物を水槽内で冷却させた後、内部温度を２５℃以下に維持しながら２０分間にわたってメタ過ヨウ素酸ナトリウム１１８ｇを小分けして加えた。前記反応混合物を室温で２時間攪拌した。薄膜クロマトグラフィーにより反応終了を確認した後、反応混合物に無水硫酸マグネシウム３６ｇを加えて２０分間攪拌した。生成した混合物をろ過して減圧下で３０℃で蒸留して溶媒を除去し、残渣を大気圧下で５５℃で蒸留して溶媒を完全に除去した。その結果得られた残渣を１０トール(ｔｏｒｒ)及び約４０で蒸留して無色液状の標題化合物６１．６ｇ(収率：８６％)を得た。
ＮＭＲ(３００ＭＨｚ，ＣＤＣｌ_３)：１．４１(ｓ，３Ｈ)，１．４７(ｓ，３Ｈ)，４．０７〜４．１９(ｍ，２Ｈ)，４．３５〜４．４０(ｍ，１Ｈ)，９．７１(ｓ，１Ｈ) Stage 2
Preparation of 2,2-dimethyl- [1,3] -dioxolane-4-carbaldehyde

After dissolving 72.4 g of the compound obtained in Step 1 in 724 ml of methyl chloride, 30 ml of saturated sodium bicarbonate was added thereto. After the mixture was cooled in a water bath, 118 g of sodium metaperiodate was added in small portions over 20 minutes while maintaining the internal temperature at 25 ° C. or lower. The reaction mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by thin film chromatography, 36 g of anhydrous magnesium sulfate was added to the reaction mixture and stirred for 20 minutes. The resulting mixture was filtered and distilled at 30 ° C. under reduced pressure to remove the solvent, and the residue was distilled at 55 ° C. under atmospheric pressure to completely remove the solvent. The resulting residue was distilled at 10 torr and about 40 to obtain 61.6 g (yield: 86%) of the title compound as a colorless liquid.
NMR (300 MHz, CDCl ₃ ): 1.41 (s, 3H), 1.47 (s, 3H), 4.07 to 4.19 (m, 2H), 4.35 to 4.40 (m, 1H) ), 9.71 (s, 1H)

Stage 3
Preparation of ethyl 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxolan-4-yl) propionate

13 ml of zinc was added to 26 ml of tetrahydrofuran, 0.51 ml of dibromoethane was further added, and the mixture was kept at 60 ° C. for 1 minute. To this mixture, 0.76 ml of chlorotrimethylsilane was added at 40 ° C. and reacted for 10 minutes. The reaction mixture was heated to 60 ° C., and a solution of 25.5 ml of ethyl bromodifluoroacetate and 30.8 g of the compound obtained in Step 2 in 39 ml of tetrahydrofuran was added dropwise thereto, and the mixture was refluxed for 30 minutes. To this was added 65 ml of diethyl ether and 260 g of ice, 260 ml of 1N hydrochloric acid was added, and the mixture was stirred until the ice was completely dissolved. The aqueous layer was extracted three times with 90 ml of diethyl ether, and the extracted organic layers were combined, washed sequentially with NaCl and 65 ml of sodium bicarbonate, dried over anhydrous magnesium sulfate, and then filtered. After removing the solvent, the residue was distilled at 10 torr to obtain 28.9 g (yield: 57%) (R: S = 3: 1) of the title compound as a colorless liquid at 130-134 ° C.
NMR (300 MHz, CDCl ₃ ): 1.31-1.52 (m, 9H), 2.67 (s, 1H, (R) —OH), 2.90 (d, 1H, (S) —OH) 3.7-4.4 (m, 6H)

を意味する。 In the following examples, the term “—OCOBiPh” or “BiPhOCO—”

Means.

HPLC analysis for compounds of formula (I) and formula (III) shows that eluent is a mixture of buffer solution and acetonitrile (65:35, v / v) (for compounds of formula (III)) or 80% acetonitrile. This was done using a YMC pack pro C18 RS (4.6 * 150 mm, 5 μm) column using the solution (when the compound of formula (I) was used). The buffer solution was prepared by mixing 7.0 g of NaClO ₄ , 1.74 g of K ₂ HPO ₄ and 1 L of water, and adding H ₃ PO ₄ thereto until the pH was 2.75.

前記製造例１で得られた化合物５０．０ｇを塩化メチレン５００ｍｌに加えた後、これにトリエチルアミン４２ｍｌ及び塩化４−ビフェニルカルボニル５１．１ｇを加えて、室温で６時間反応させた。この混合物に１Ｎ塩酸３６０ｍｌを加えた後、有機層を水、飽和重炭酸ナトリウム及びＮａＣｌ溶液１８０ｍｌにより順次洗浄し、硫酸マグネシウムで乾燥した。残渣をろ過した後、減圧下で蒸留して淡黄色の液状の標題化合物８３．７ｇ(収率：９８％)を得た。
ＮＭＲ(３００ＭＨｚ，ＣＤＣｌ_３)：１．２５〜１．７４(ｍ，９Ｈ)，４．１１〜４．１９(ｍ，２Ｈ)，４．３０〜４．３６(ｍ，２Ｈ)，４．５６〜４．５８(ｍ，２Ｈ)，５．７２〜５．８３(ｄｄｄ，１Ｈｘ１／３)，５．８８〜６．０２(ｄｄｄ，１Ｈｘ２／３)，７．４２〜７．５３(ｍ，３Ｈ)，７．６３〜７．７３(ｄｄ，４Ｈ)，８．１５〜８．１７(ｄ，２Ｈ) Example 1
Preparation of ethyl 2,2-difluoro-3- (4-biphenylcarbonyl) oxy-3- (2,2-dimethyl- [1,3] dioxolan-4-yl) propionate (compound of formula (IV); R = 4-biphenylcarbonyl)

After adding 50.0 g of the compound obtained in Production Example 1 to 500 ml of methylene chloride, 42 ml of triethylamine and 51.1 g of 4-biphenylcarbonyl chloride were added thereto and reacted at room temperature for 6 hours. After adding 360 ml of 1N hydrochloric acid to this mixture, the organic layer was washed successively with water, saturated sodium bicarbonate and 180 ml of NaCl solution and dried over magnesium sulfate. The residue was filtered and distilled under reduced pressure to obtain 83.7 g (yield: 98%) of the title compound as a pale yellow liquid.
NMR (300 MHz, CDCl ₃ ): 1.25 to 1.74 (m, 9H), 4.11 to 4.19 (m, 2H), 4.30 to 4.36 (m, 2H), 4.56 -4.58 (m, 2H), 5.72-5.83 (ddd, 1Hx1 / 3), 5.88-6.02 (ddd, 1Hx2 / 3), 7.42-7.53 (m, 3H), 7.63-7.73 (dd, 4H), 8.15-8.17 (d, 2H)

方法Ａ
前記実施例１で得られた化合物８３．８ｇをテトラヒドロフラン及びメタノールの混合物(２：３、ｖ／ｖ)１．４Ｌに加え、これに水７５０ｍｌに溶解させた炭酸カリウム１０７ｇを加えた。前記混合物を３０分間攪拌した後、減圧下で有機溶媒を除去した。ろ過した後、生成された固体をエーテル１００ｍｌを加え、攪拌し、ろ過した後、エーテルで洗浄し、これを乾燥して白色固体の標題化合物６０．１ｇ(収率：７０％)を得た。
ＨＰＬＣ：Ｒ−異性体９９．８６％、Ｓ−異性体０．１１％
ＮＭＲ(３００ＭＨｚ，ＤＭＳＯ)：１．０７(ｓ，３Ｈ)，１．２２(ｓ，３Ｈ)，３．９９(ｔ，１Ｈ)，４．１１(ｔ，１Ｈ)，４．４９(ｔ，１Ｈ)，５．８８(ｄｄｄ，１Ｈ)，７．３８〜７．５４(ｍ，３Ｈ)，７．７５(ｄ，２Ｈ)，７．８５(ｄ，２Ｈ)，８．０７(ｄ，２Ｈ) Example 2
Preparation of potassium 2,2-difluoro-3R- (4-biphenylcarbonyl) oxy-3- (2,2-dimethyl- [1,3] dioxolan-4-yl) propionate (compound of formula (III); R = 4-biphenylcarbonyl)

Method A
83.8 g of the compound obtained in Example 1 was added to 1.4 L of a mixture of tetrahydrofuran and methanol (2: 3, v / v), and 107 g of potassium carbonate dissolved in 750 ml of water was added thereto. After stirring the mixture for 30 minutes, the organic solvent was removed under reduced pressure. After filtration, the resulting solid was added with 100 ml of ether, stirred, filtered, washed with ether, and dried to give 60.1 g (yield: 70%) of the title compound as a white solid.
HPLC: R-isomer 99.86%, S-isomer 0.11%
NMR (300 MHz, DMSO): 1.07 (s, 3H), 1.22 (s, 3H), 3.99 (t, 1H), 4.11 (t, 1H), 4.49 (t, 1H) ), 5.88 (ddd, 1H), 7.38-7.54 (m, 3H), 7.75 (d, 2H), 7.85 (d, 2H), 8.07 (d, 2H)

Method B
94.0 g of the compound obtained in Example 1 was added to 600 ml of a mixture of tetrahydrofuran and methanol (1: 1, v / v), and then 54.4 g of potassium carbonate dissolved in 500 ml of water was added thereto. The mixture was stirred for 1 hour, washed twice with 500 ml of hexane, extracted with 500 ml of ethyl acetate, and then the solvent was removed under reduced pressure. The resulting solid was mixed with 100 ml of water and 300 ml of i-propyl alcohol, heated until dissolved, and 700 ml of i-propyl alcohol was added to this mixture. The resulting mixture was recrystallized by holding at room temperature for 2 hours, and the resulting solid was filtered, washed with i-propyl alcohol and dried to give 62.5 g (yield) of the title compound as a white solid. : 65%).
HPLC: R-isomer 99.91%, S-isomer 0.06%
NMR (300 MHz, DMSO): 1.07 (s, 3H), 1.22 (s, 3H), 3.99 (t, 1H), 4.11 (t, 1H), 4.49 (t, 1H) ), 5.88 (ddd, 1H), 7.38-7.54 (m, 3H), 7.75 (d, 2H), 7.85 (d, 2H), 8.07 (d, 2H)

Example 3
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-urose-5-benzoyl-3- (4-phenyl) benzoate (compound of formula (I); R = 4-biphenyl Carbonyl, R ³ = Benzoyl)
Method A: Method for producing the product of each stage separately
Stage 1
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-urose-3- (4-phenyl) benzoate (compound of formula (II); R = 4-biphenylcarbonyl)

10 g of the compound obtained in Example 2 was dispersed in 60 ml of acetonitrile, 2.5 ml of 12N hydrochloric acid was added thereto, and the mixture was refluxed for 6 hours. To this was added 60 ml of toluene, and the reaction mixture was distilled to remove the solvent. The above process was repeated twice. 100 ml of ether was added to the resulting residue, followed by filtration to remove KCl, and distillation under reduced pressure to remove the solvent. The produced residue was added to 50 ml of ether, and 100 ml of hexane was added thereto to induce recrystallization of the solid. The solid was collected by filtration (first batch of solid), and the filtrate was distilled under reduced pressure, followed by a second recrystallization step using 20 ml of ether and 50 ml of hexane to obtain a second batch of solid. The solids were combined and dried under vacuum to give 5.9 g (yield: 75%) of the title compound as a white solid.
NMR (300 MHz, CDCl ₃ ): 1.8 to 2.4 (brds, 1H), 3.78 to 4.02 (dd, 1H), 4.11 to 4.13 (dd, 1H), 4.71 To 4.73 (m, 1H), 5.79 to 5.87 (m, 1H), 7.44 to 7.54 (m, 3H), 7.64 to 7.66 (d, 2H), 7 21 to 7.75 (d, 2H)
Melting point (mp): 107-111 ° C

Stage 2
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-urose-5-benzoyl-3- (4-phenyl) benzoate

15.0 g of the compound obtained in the above Step 1 was added to 150 ml of methylene chloride, and then stirred at room temperature, 6.9 ml of pyridine was added dropwise thereto, and 7.4 ml of benzoyl chloride was dissolved in 40 ml of methylene chloride. The mixed solution was gradually added while maintaining a temperature of 5 to 10 ° C. After the reaction mixture was kept at room temperature for 7 hours, 105 ml of 1N hydrochloric acid was added thereto to neutralize pyridine in the mixture, and water was added thereto to separate the organic layer. The organic layer was separated and then washed successively with saturated sodium bicarbonate and 100 ml of NaCl, dried over magnesium sulfate and filtered. The filtrate was kept under reduced pressure to give a pale yellow solid. The obtained solid was recrystallized from a mixture of ether and hexane (5: 1, v / v) to obtain 16.8 g of the title compound (yield: 86%).
NMR (300 MHz, CDCl ₃ ): 4.90 to 4.75 (ddd, 2H), 5.10 (dd, 1H), 5.87 (ddd, 1H), 7.65 to 7.50 (m, 5H) ), 7.78-7.67 (m, 3H), 7.81 (d, 2H), 8.13 (d, 2H), 8.23 (d, 2H)
Melting point (mp): 130-131 ° C
HPLC purity: 99.21% (no threo isomer detected)

アセトニトリル２３２ｍｌを前記実施例２で得られた化合物３８．８ｇ及び１２Ｎ塩酸９．２ｍｌと混合した後、前記混合物を６時間還流させた。これにトルエン４６４ｍｌを加えた後、反応混合物を温度が１００℃以上となるまで蒸留して水及びアセトニトリルを除去した。生成された濃縮物をろ過し、減圧下で保持させて泡状(ｆｏａｍ−ｓｈａｐｅｄ)の固体を得た。前記固体を酢酸エチル３００ｍｌに溶解させた後、攪拌しながらこれにピリジン１４ｍｌを加え、これに酢酸エチル７５ｍｌに塩化ベンゾイル１５ｍｌを溶解させた混合溶液を加えた。前記混合物を室温で６時間保持させた後、１Ｎ塩酸２１０ｍｌを加えてピリジンを中和させた。有機層を分離した後、水、飽和重炭酸ナトリウム、及びＮａＣｌ溶液１５０ｍｌずつで順次洗浄し、硫酸マグネシウムで乾燥した後、減圧下で淡黄色の固体を得た。得られた前記固体をエーテルとヘキサンとの混合物(５：１、ｖ／ｖ)から再結晶化して白色固体の標題化合物２８．４ｇ(収率：７２％)を得た。
ＮＭＲ(３００ＭＨｚ，ＣＤＣｌ_３)：４．９０〜４．７５(ｄｄｄ，２Ｈ)，５．１０(ｄｄ，１Ｈ)，５．８７(ｄｄｄ，１Ｈ)，７．６５〜７．５０(ｍ，５Ｈ)，７．７８〜７．６７(ｍ，３Ｈ)，７．８１(ｄ，２Ｈ)，８．１３(ｄ，２Ｈ)，８．２３(ｄ，２Ｈ)
融点(ｍ．ｐ)：１３０〜１３１℃
ＨＰＬＣ純度：９９．０５％(トレオ異性体は検出されなかった) Method B: Manufacturing method in situ

After mixing 232 ml of acetonitrile with 38.8 g of the compound obtained in Example 2 and 9.2 ml of 12N hydrochloric acid, the mixture was refluxed for 6 hours. To this was added 464 ml of toluene, and then the reaction mixture was distilled until the temperature reached 100 ° C. or higher to remove water and acetonitrile. The resulting concentrate was filtered and held under reduced pressure to give a foam-shaped solid. After the solid was dissolved in 300 ml of ethyl acetate, 14 ml of pyridine was added thereto while stirring, and a mixed solution in which 15 ml of benzoyl chloride was dissolved in 75 ml of ethyl acetate was added thereto. The mixture was kept at room temperature for 6 hours, and 210 ml of 1N hydrochloric acid was added to neutralize pyridine. The organic layer was separated, washed successively with 150 ml of water, saturated sodium bicarbonate, and NaCl solution, dried over magnesium sulfate, and a pale yellow solid was obtained under reduced pressure. The obtained solid was recrystallized from a mixture of ether and hexane (5: 1, v / v) to obtain 28.4 g (yield: 72%) of the title compound as a white solid.
NMR (300 MHz, CDCl ₃ ): 4.90 to 4.75 (ddd, 2H), 5.10 (dd, 1H), 5.87 (ddd, 1H), 7.65 to 7.50 (m, 5H) ), 7.78-7.67 (m, 3H), 7.81 (d, 2H), 8.13 (d, 2H), 8.23 (d, 2H)
Melting point (mp): 130-131 ° C
HPLC purity: 99.05% (no threo isomer detected)

Example 4
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-urose-3,5-di- (4-phenyl) benzoate (compounds of formula (I); R and R ³ = 4-biphenylcarbonyl)
Method A: Method of separately producing each product in each stage

前記実施例２の方法Ａの段階１における工程を繰り返して標題化合物を得た(収率：７５％)。 Stage 1
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-urose-3- (4-phenyl) benzoate (compound of formula (II); R = 4-biphenylcarbonyl)

The title compound was obtained by repeating the process in Step 1 of Method A of Example 2 (yield: 75%).

Stage 2
Preparation of D-erythro-2-deoxy-2,2-difluoro-pentofuranose-1-urose-3,5-di- (4-phenyl) benzoate

To 300 ml of chloroform was added 20 g of the compound obtained in the above step 1, 9.5 ml of pyridine was added with stirring at room temperature, and a mixed solution of 10.1 ml of benzoyl chloride dissolved in 55 ml of chloroform was added thereto. The mixture was held at room temperature for 6 hours, and then residual pyridine was neutralized with 140 ml of 1N hydrochloric acid. The organic layer was separated, washed successively with 150 ml each of water, saturated sodium bicarbonate and NaCl, dried over magnesium sulfate, and kept under reduced pressure to obtain a pale yellow solid. The solid was recrystallized from a mixed solution of ethyl acetate and hexane (3: 1, v / v) to obtain 21.8 g (yield: 72%) of the title compound as a white solid.
NMR (300 MHz, CDCl ₃ ): 4.72 to 4.79 (m, 2H), 5.03 (q, 1H), 5.84 to 5.76 (m, 1H), 7.48 to 7.44 (m, 6H), 7.72-7.60 (m, 8H), 8.15-8.07 (m, 4H)
Melting point (mp): 137-139 ° C
HPLC purity: 98.95% (no threo isomer detected)

前記実施例２で得られた化合物４０．０ｇをアセトニトリル２４０ｍｌに加え、これに１２Ｎ塩酸１０ｍｌを加えて、混合物を６時間還流させた。これにトルエン２５０ｍｌを加えた後、反応混合物を蒸留して水及びアセトニトリルを除去し、室温に冷却し、ろ過し、減圧下で保持させることで中間体として５−ヒドロキシ−１−オキソリボース化合物を得た。前記中間体を酢酸エチル４８０ｍｌに溶解させた後、これにピリジン２１．８ｍｌと塩化４−ビフェニルカルボニル３９ｇとの混合物を加え、室温で１２時間保持させた。生成した混合物に１Ｎ塩酸３２０ｍｌを加えて残余ピリジンを中和させ；有機層を分離し、水、飽和重炭酸ナトリウム、及びＮａＣｌ １６０ｍｌずつで順次洗浄した後、乾燥し、ろ過した。ろ液を減圧下で保持させることで溶媒を除去し、残渣を酢酸エチル及びヘキサンの混合物(３：１、ｖ／ｖ)から再結晶して白色固体の標題化合物３１．９ｇ(収率：６５％)を得た。
ＮＭＲ(３００ＭＨｚ，ＣＤＣｌ_３)：４．７２〜４．７９(ｍ，２Ｈ)，５．０３(ｑ，１Ｈ)，５．８４〜５．７６(ｍ，１Ｈ)，７．４８〜７．４４(ｍ，６Ｈ)，７．７２〜７．６０(ｍ，８Ｈ)，８．１５〜８．０７(ｍ，４Ｈ)
融点(ｍ．ｐ)：１３７〜１３９℃
ＨＰＬＣ純度：９８．３３％(トレオ異性体は検出されなかった) Method B: Manufacturing method in situ

40.0 g of the compound obtained in Example 2 was added to 240 ml of acetonitrile, 10 ml of 12N hydrochloric acid was added thereto, and the mixture was refluxed for 6 hours. After adding 250 ml of toluene to this, the reaction mixture was distilled to remove water and acetonitrile, cooled to room temperature, filtered and held under reduced pressure to give 5-hydroxy-1-oxoribose compound as an intermediate. Obtained. The intermediate was dissolved in 480 ml of ethyl acetate, and then a mixture of 21.8 ml of pyridine and 39 g of 4-biphenylcarbonyl chloride was added thereto and kept at room temperature for 12 hours. The resulting mixture was added with 320 ml of 1N hydrochloric acid to neutralize the remaining pyridine; the organic layer was separated, washed sequentially with 160 ml each of water, saturated sodium bicarbonate, and NaCl, then dried and filtered. The filtrate was kept under reduced pressure to remove the solvent, and the residue was recrystallized from a mixture of ethyl acetate and hexane (3: 1, v / v) to give 31.9 g of the title compound as a white solid (yield: 65 %).
NMR (300 MHz, CDCl ₃ ): 4.72 to 4.79 (m, 2H), 5.03 (q, 1H), 5.84 to 5.76 (m, 1H), 7.48 to 7.44 (m, 6H), 7.72-7.60 (m, 8H), 8.15-8.07 (m, 4H)
Melting point (mp): 137-139 ° C
HPLC purity: 98.33% (no threo isomer detected)

Claims (9)

(i) reacting a compound of formula (V) with a biphenylcarbonyl derivative to obtain a compound of formula (IV) having a 3-hydroxy group protected with a biphenylcarbonyl group;
(ii) reacting the compound of the formula (IV) with a base in a mixed solvent essentially containing water to obtain a 3R-carboxylate enantiomer of the formula (III) by filtration ;
(iii) reacting the compound of formula (III) with an acid to give a 5-hydroxy-1-oxoribose derivative of formula (II); and
(iv) a 2,2-difluoro-2-deoxy-1-oxoribose derivative of formula (I), comprising the step of protecting the 5-hydroxy group of the compound of formula (II) with R ³ Manufacturing method:

In the above formula,
R is

Is;
R ¹ is methyl or ethyl;
R ² is C _1-3 alkyl;
R ³ is benzoyl or

Is;
R ⁴ is a phenyl; and M is sodium or potassium.   The process according to claim 1, wherein the biphenylcarbonyl group of step (i) is 2-biphenylcarbonyl or 4-biphenylcarbonyl.   The mixed solvent essentially containing water used in the step (ii) is water, tetrahydrofuran, dioxane, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, methanol, ethanol, propanol, isopropanol, dimethylacetamide, dimethylformamide, dimethylsulfoxide. The method according to claim 1, wherein the mixture is an organic solvent selected from the group consisting of ethyl acetate and mixtures thereof. Base is sodium carbonate acid used in the step (ii), sodium bicarbonate, sodium hydroxide, potassium carbonate, potassium bicarbonate, claim 1, characterized in that it is selected from the group consisting of potassium hydroxide, and mixtures thereof The method described in 1.   The process according to claim 4, characterized in that the base used in step (ii) is potassium carbonate. The acid used in the step (iii) is selected from the group consisting of 1 to 12N HCl, 1 to 9N H ₂ SO ₄ , methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid. The method according to claim 1.   The method of claim 6, wherein the acid used in step (iii) is 12N HCl.   The process according to claim 1, wherein the acid used in step (iii) is used in an amount of 1.1 to 1.5 equivalents relative to the compound of formula (II). 3R-carboxylate optical isomer of the following formula (III):

In the above formula,
R is

Is;
R ¹ is methyl or ethyl;
R ⁴ is a phenyl; and M is sodium or potassium.